Mitochondrial decay is an intrinsic part of aging and age-associated chronic diseases, especially neurodegenerative pathologies such as Parkinson?s and Alzheimer?s diseases (AD). In particular, mitochondrial matrix glutathione (mGSH), which is essential for normal mitochondrial function, declines with age and in AD where mGSH loss has been identified as one of the earliest hallmarks associated with disease onset. The reason mGSH is so vital is that mitochondria do not synthesize GSH; rather, mGSH is supplied from the cytosol via slow facilitated transport. This lack of equilibrium with the cytosol severely challenges the cell's ability to maintain sufficient mGSH levels when its rate of oxidation exceeds supply. Such constraints to maintaining mGSH thus constitute a key barrier to creating an effective GSH-restoring treatment. There is no current clinical therapy that remediates mGSH. Compounds that increase cellular GSH do not sustainably affect the mitochondrial GSH pool. The lack of mitochondrial GSH remediators thus represents a distinct barrier to limiting the degree of mitochondrial dysfunction during a variety of pathophysiological conditions that occur in aging. We created a novel compound, triphenylphosphonium-GSH (TPP-GSH) in an attempt to overcome the obstacles for a mGSH therapy. Our promising preliminary findings show that fully water soluble TPP-GSH elevates mGSH levels in isolated rat hepatocytes, and restores mitochondrial structure and function in transgenic mice that develop Alzheimer?s Disease-like pathology. We propose that TPP-GSH will supply GSH to mitochondria and serve as a mGSH-restoring and -augmenting therapy. We will address this proposal in two Aims where: Aim 1 will define the bioavailability and tissue distribution characteristics of TPP-GSH. We will establish a non-toxic TPP-GSH dose-range (both ip and orally) for male and female C57BL/6J mice at 3-5 weeks (young) and 18 months (old) of age. Cohorts of young and old mice of both sexes will be treated with isotopically labeled TPP-GSH at the Maximum Tolerated Dose (MTD) for each group prior to sacrifice and to determine TPP-GSH tissue distribution by LC-mass spectrometry. The amount of TPP-GSH accumulating in the mitochondrial matrix will also be defined. Aim 2 will determine whether TPP-GSH maintains or improves mitochondrial function in 5xFAD mice. Presenilin-mutant mice (5xFAD) which rapidly develop A?-mediated mitochondrial damage followed by neurocognitive deficits will be used to test the extent that TPP-GSH preserves hippocampal mitochondrial function. TPP-GSH will be given to both sexes of 5xFAD mice (& wildtype [WT] controls) at the MTD starting at weaning. Treatment will continue up to 6 months when severe mitochondrial decay and neurocognitive decline are typically evident. Throughout, mice will be tested for memory and learning, and also mitochondrial function assessed (ultrastructure, bioenergetic reserve, & oxidant leakage). Similar measures of function will be made in 5xFAD and WT given TPP-GSH starting at 6 months to test whether TPP-GSH may also act as an interventional therapy to interdict neurocognitive decline.